T h e new england journal o f medicine Review article Medical Progress Infection in Solid-Organ Transplant Recipients Jay A. Fishman, M.D. ncreasingly potent immunosuppressive agents have dramatically From the Transplant Infectious Disease reduced the incidence of rejection of transplanted organs while increasing pa- and Compromised Host Program, Massa- 1,2 chusetts General Hospital, and Harvard tients’ susceptibility to opportunistic infections and cancer. At the same time, Medical School, Boston. Address reprint I requests to Dr. Fishman at the Transplant patterns of opportunistic infections after transplantation have been altered by routine antimicrobial prophylaxis for Pneumocystis carinii (also called P. jirovecii) and cytomega- Infectious Disease and Compromised Host Program, Massachusetts General lovirus. These patterns have also been altered by the emergence of new clinical syn- Hospital, 55 Fruit St., GRJ 504, Boston, dromes (e.g., polyomavirus type BK nephropathy) and by infections due to organisms MA 02114, or at [email protected]. with antimicrobial resistance. New quantitative molecular and antigen-based micro- N Engl J Med 2007;357:2601-14. biologic assays detect previously unrecognized transplantation-associated pathogens Copyright © 2007 Massachusetts Medical Society. such as lymphocytic choriomeningitis virus. These assays are used in the manage- ment of common infections such as those due to cytomegalovirus and Epstein–Barr virus (EBV). In this article, I review general concepts in the management of trans- plantation-associated infections and discuss recent advances and challenges. GENERAL CONCEPTS It is more difficult to recognize infection in transplant recipients than it is in persons with normal immune function, since signs and symptoms of infection are often di- minished. In addition, noninfectious causes of fever, such as allograft rejection, may develop in transplant recipients. Antimicrobial therapy frequently has toxic effects that may involve interactions with immunosuppressive agents. The spectrum of po- tential pathogens is broad, and infection often progresses rapidly. Early and specific microbiologic diagnosis is essential for guiding treatment and minimizing nones- sential drug therapy. Invasive diagnostic procedures are often required for accurate and timely diagnosis. RISK OF INFECTION The risk of infection after transplantation changes over time, particularly with mod- ifications in immunosuppression. Unfortunately, no assays accurately measure a pa- tient’s risk of infection. Currently, therefore, the clinician assesses a recipient’s risk of infection while considering the risk of allograft rejection, the intensity of immuno- suppression, and other factors that may contribute to his or her susceptibility to in- fection. Prophylactic strategies are based on the patient’s known or likely exposures to infection according to the results of serologic testing and epidemiologic history. The risk of infection in the transplant recipient is a continuous function of the in- terplay between these factors. Epidemiologic Exposures Epidemiologic exposures can be divided into four overlapping categories: donor-derived infections, recipient-derived infections, nosocomial infections, and community infec- tions. n engl j med 357;25 www.nejm.org december 20, 2007 2601 T h e new england journal o f medicine Donor-Derived Infections and Screening Transplanted organs facilitate the transmission of A infections from organ donors. Mandatory report- ing of transplantation-associated infections has increased awareness of this problem. Most often, these infections (e.g., cytomegalovirus infection, tuberculosis, and Trypanosoma cruzi infection) are latent in transplanted tissues. Transmission may also be due to active donor infection such as vire- mia or bacteremia that was undiscovered at the time of organ procurement (Fig. 1A).3 Organ donors also may become infected with nosocomial organisms that are resistant to rou- tine surgical antimicrobial prophylaxis, and they may transmit these organisms (e.g., vancomycin- B resistant enterococcus and azole-resistant candida species) to recipients.4-6 Clusters of infections derived from deceased donors have been described, including transplan- tation-associated West Nile virus infection, lym- phocytic choriomeningitis virus infection, rabies, human immunodeficiency virus (HIV) infection, and Chagas’ disease.3,7-10 In recent outbreaks of West Nile virus infection, lymphocytic choriomen- ingitis virus infection, and rabies, signs of infec- tious encephalitis in organs from deceased donors were masked by unrelated acute neurologic events and thus were not recognized. Figure 1. Effect of Donor-Derived Infection or Graft Nonspecific signs such as altered mental status Injury on the Risk of Infection after Transplantation. or abnormal results of liver-function tests may be Panel A is a chest radiograph showing pneumonia result- ing ICMfrom donor-derivedAUTHOR Fishman herpes simplex virusRET infection.AKE 1st the sole basis on which to investigate potential 2nd FeverREG and F pneumoniaFIGURE 1a&b developed of 5 in a kidney-transplant donor-related infections. In the normal host, in- CASE 3rd recipient 3 TITLEdays after a technically successful Revisedtransplanta- fections due to West Nile virus or lymphocytic tion,EMail and the patient had abnormalLine results4-C on liver-func- Enon SIZE choriomeningitis virus are generally self-limited. tion tests. BloodARTIST :andmst sputumH/T containedH/T herpes simplex FILL Combo 16p6 However, in organ-transplant recipients with these virus. This virus was also detected in donor serum by means of a polymerase-chain-reactionAUTHOR, PLEASE NOTE: assay. Recipients infections, rapid progression, permanent neuro- Figure has been redrawn and type has been reset. logic damage, and death are more common be- of the liver, heart, andPlease other check kidney carefully from. the same donor were symptomatic and were treated successfully with an- cause of the broad immunologic deficits that are tiviralJOB: therapy. 35725 Panel B is a computedISSUE: tomographic12-20-07 scan present after transplantation. showing a liver abscess at the site of an ischemic graft in- The screening of transplant donors for infec- jury. The patient had persistently and mildly abnormal tion is limited by the available technology and by liver-function tests (elevated alkaline phosphatase and to- the short period during which organs from de- tal bilirubin levels) after undergoing technically success- ful orthotopic liver transplantation with early graft isch- ceased donors can be used. At present, the routine emia. Three years later, fever and chills developed, and evaluation of donors for infectious disease gener- a heterogeneous 6-cm abscess (arrow) with intrahepatic ally relies on antibody detection with the use of biliary ductal dilatation was detected. Therapy included serologic tests for common infections (Fig. 2). percutaneous drainage and administration of antimicro- Since seroconversion may not occur during acute bial agents for organisms including vancomycin-resistant Enterococcus faecalis and Candida glabrata. infections and the sensitivity of these tests is not 100%, some active infections remain undetected. Some organs that contain unidentified pathogens curement organizations. Augmented screening is will inevitably be implanted. Improved donor recommended on a regional basis for endemic or screening will require the use of more sensitive epidemic infections such as West Nile virus infec- (e.g., molecular) and rapid assays by organ-pro- tion, Chagas’ disease, and strongyloidiasis.11 2602 n engl j med 357;25 www.nejm.org december 20, 2007 Medical Progress Some documented infections, such as sepsis and HIV infection, preclude organ donation. Or- Donor Screening gans from donors with specified known infec- Epidemiologic history Serologic testing for VDRL, HIV, tions may be considered for specific recipients — CMV, EBV, HSV, VZV, HBV provided there is appropriate informed consent (HBsAg, anti-HBsAg), and HCV Microbiologic testing of blood — based on the urgency of the need for transplan- and urine Risk Assessment tation and the availability of effective antimicro- Chest radiography Higher risk of infection Known infections (appropriate Induction therapy with lympho- bial therapies. For example, some livers from do- therapy?) cyte depletion nors who were seropositive for Chagas’ disease Possible infections (e.g., encepha- Pulsed-dose corticosteroids litis, sepsis) Plasmapheresis have been used successfully with benznidazole Special serologic testing, nucleic High risk of rejection prophylaxis in regions where the disease is en- acid assays, or antigen detection Early graft rejection 12 based on epidemiologic factors Graft dysfunction demic. Similarly, although organs from donors and recent exposures (e.g., toxo- Active or latent infection in the infected with the hepatitis B virus (HBV) and who plasma, West Nile virus, HIV, donor or recipient HCV) Technical complications had test results that were positive for antibodies Anastomotic leak against hepatitis B core antigen and negative for Bleeding antibodies against hepatitis B surface antigen were Wound infection or poor Recipient Screening healing Prolonged intubation rejected in the past, they are currently used for Epidemiologic history Prolonged use of surgical, Vaccination history some recipients who have been vaccinated or who vascular, or urinary Serologic testing for VDRL, HIV, catheters were previously